Project Summary Type 1 diabetes (T1D) results from the immune mediated destruction of insulin producing beta cells within the pancreas. T1D is increasing in incidence and predictable with the measurement of T1D associated autoantibodies from the peripheral blood; however, there are no means to prevent the disease. Despite the availability of exogenous insulin, many patients and families have difficulty attaining normal blood glucose control and thus remain at risk for devastating acute (hypoglycemia) and long-term complications. As such, it is estimated that T1D accounts for $14.9 billion in healthcare costs each year. To lessen the burden of disease and to better address the heterogeneity of the T1D, more specific and personalized therapies that treat the underlying autoimmunity of T1D are needed for disease prevention. To address this gap, ImmunoMolecular Therapeutics (IMT) was founded to develop small molecule drugs such as the D enantiomer of methyldopa (MDOPA) as an oral immunotherapeutic approach for the preservation of residual beta cell function in T1D. Human leukocyte antigen (HLA) genes confer significant genetic risk for T1D with recent studies implicating HLA-DQ8 restricted T cells in disease pathogenesis, making it an important therapeutic target. DQ8 is present in ~50-60% of all T1D patients and those at risk. Previously, a novel pathway to control the underlying T cell mediated autoimmunity in T1D was identified, which involves blocking DQ8 with Methyldopa (Aldomet). L- MDOPA is an FDA approved drug for both children and adults with a well-established safety profile as it has been used clinically over the last 50 years to treat hypertension and pregnancy induced hypertension. A recent Phase Ib dose escalation clinical trial in recently diagnosed T1D patients (n=20) with the HLA-DQ8 gene indicated that L-MDOPA was safe, tolerable and confirmed the mechanism of action, i.e., inhibited DQ8 peptide presentation to T cells including primary insulin specific T cells. However, there are limitations with L-MDOPA in terms of dosing frequency (twice to three times daily) and side effects. The D enantiomer of methyldopa overcomes these limitations. Unlike the L enantiomer, the D enantiomer is likely not metabolized thereby eliminating many side effects as well as the anti-hypertensive action, and has more potency to block DQ8 in rodent experiments. While there are published reports using D-MDOPA in humans many decades ago, those studies were not done to today?s scientific standards and are inadequate to qualify D-MDOPA for an IND. To advance D-MDOPA to the stage of an IND and further delineate the drug target effect, we propose the following specific aims: (1) To evaluate the direct drug target effect (on and off rate to HLA-DQ8) for D-MDOPA compared to L-MDOPA, and (2) To evaluate initial toxicology, pharmacology and metabolic properties of D-MDOPA. These studies along with other preclinical work will establish the pharmacology, safety and tolerability necessary for IMT to file an IND for D-MDOPA and then initiate human Phase 1 trials of this personalized medicine approach to treating type 1 diabetes.